Method and apparatus for skin absorption enhancement and transdermal drug delivery

ABSTRACT

A system for enhancing absorption of a substance to be provided on a region of a patient&#39;s skin, includes a probe configured to provide the substance to the region of the patient&#39;s skin, the probe including a flexible tape with a plurality of cavities, and with an electrically conductive element, such as a conductive wire, provided at one end of each of the cavities. A substance holding material, such as gauze stripes, temporarily holds the substance to be provided on the region of the patient&#39;s skin, the substance holding material being provided in each of the cavities. A pulse generator generates a sequence of bursts of electrical pulses to the electrically conductive elements provided within the cavities, so as to provide the bursts of electrical pulses to the region of the patient&#39;s skin.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application claims priority to U.S. Provisional Application60/281,808, filed Apr. 6, 2001, and whereby this application is adivisional of U.S. patent application Ser. No. 11/657,551, filed Jan.25, 2007 (now U.S. Pat. No. 7,520,875), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/992,597,filed Nov. 19, 2004 (now U.S. Pat. No. 7,496,401), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/784,913,filed Feb. 24, 2004 (now U.S. Pat. No. 7,083,580), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/448,468,filed May 30, 2003 (now U.S. Pat. No. 6,980,854), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/397,533,filed Mar. 27, 2003 (now U.S. Pat. No. 7,010,343), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/201,644,filed Jul. 24, 2002 (now U.S. Pat. No. 6,748,266), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 10/074,234,filed Feb. 14, 2002 (now U.S. Pat. No. 6,743,215), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 09/942,044,filed Aug. 30, 2001 (now U.S. Pat. No. 6,687,537), which in turn is acontinuation-in-part of U.S. patent application Ser. No. 09/922,927,filed Aug. 7, 2001 (now U.S. Pat. No. 6,535,761), each of which isincorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

A. Field of the Invention

The invention relates to application of a substance to a patient's skin,whereby the substance is an ascorbic acid, lidocaine, collagen, or othertype of skin treatment substance.

B. Description of the Related Art

It is known that an electrical pulse applied to the skin is useful inorder to increase the absorption of a substance previously applied tothe skin, whereby this technique is known as electroporation. Such asubstance to be applied to the skin may be a liquid, a gel, a lotion, ora cream, for example.

It is desired to provide an apparatus and a method to increase theabsorption of a substance to be applied to the skin, in order to obtainan increased (e.g., moisturizing) affect of the substance applied to theskin, as well as to obtain a fairly even absorption of the substance tothe skin.

SUMMARY OF THE INVENTION

The present invention is directed to an apparatus and a method forenhancing the absorption of a substance to be applied on the skin.

According to one aspect of the invention, there is provided a system forenhancing absorption of a substance to be provided on a region of apatient's skin, which includes a probe configured to provide thesubstance to the region of the patient's skin, the probe including aflexible tape with a plurality of cavities, and with an electricallyconductive element provided at one end of each of the cavities. Thesystem also includes a substance holding material configured totemporarily hold the substance to be provided on the region of thepatient's skin, the substance holding material being provided in each ofthe cavities. The system further includes a pulse generator configuredto generate a sequence of bursts of electrical pulses to theelectrically conductive elements provided within the cavities, so as toprovide the bursts of electrical pulses to the region of the patient'sskin.

According to another aspect of the invention, there is provided a methodof transdermal drug delivery to be provided to a patient's skin, whichincludes performing a dermabrasion treatment of the patient's skin so asto lower a skin impedance to below a first value. The method alsoincludes providing, by way of a probe that comprises a flexible tape, aplurality of cavities, and a substance holding material provided in eachof the cavities and which holds a drug to be delivered to the patient'sskin, at least one burst of electrical pulses to the patient's skin thathas been dermabrasion treated. The method further includes controllingan amount of current to be applied to the patient's skin in the at leastone burst of electrical pulses.

According to yet another aspect of the invention, there is provided anapparatus for performing transdermal drug delivery to be provided to apatient's skin. The apparatus includes a probe having a plurality ofelectrodes on a head portion of the probe, the plurality of electrodesbeing configured to apply a plurality of bursts of electronic pulses tothe patient's skin at a same time a drug is applied to the patient'sskin, and the plurality of electrodes being configured to apply eitheralternate-polarity square pulses or sinusoidal pulses to the patient'sskin in between adjacent ones of the plurality of bursts of electronicpulses. The probe includes a flexible tape with a plurality of cavitiesin which a substance holding material is disposed in each of thecavities, the substance holding material holding the drug to be appliedto the patient's skin.

During operation, electrical pulses are provided to the skin by way ofthe electrodes on the head of the probe, and, at the same time,mechanical vibrations are provided to the skin by way of the vibratinghead portion, whereby a substance to be applied to the skin is disposedwithin the trough surrounding the central electrode. The substance isabsorbed within the skin due to the skin pores opening up as a result ofthe electrical pulses and mechanical vibrations being applied to theskin at the same time. Alternatively, only electrical pulses areprovided to the skin, which may not provide as good a skin absorptioneffect as using both electrical pulses and mechanical vibrations, butwhich provides a cheaper implementation which is suitable for certainsituations. Also, gauze pads may be provided on the probe, whereby thegauze pads are soaked with a particular solution or solutions (e.g.,hydrogel, lidocaine, or both) to be applied to the patient's skin.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing advantages and features of the invention will becomeapparent upon reference to the following detailed description and theaccompanying drawings, of which:

FIG. 1A is a side view of a vibration mechanism that is disposed withinan apparatus according to the present invention;

FIG. 1B is a front view of the vibration mechanism of FIG. 1A;

FIG. 2A shows an array of electrodes provided on an outer surface of thevibration plate that faces the skin, according to a first embodiment ofthe invention;

FIG. 2B shows an array of electrodes provided on an outer surface of thevibration plate that faces the skin, according to a second embodiment ofthe invention;

FIG. 2C shows an array of electrodes provided on an outer surface of thevibration plate that faces the skin, according to a third embodiment ofthe invention;

FIG. 3 shows a side view of a head of a probe that is used to provideboth electrical and mechanical stimulation to the skin, in order to havea substance previously applied to the skin to be absorbed better,according to the invention;

FIG. 4 shows an electrical diagram of a pulse generator that provideselectrical pulses to an array of electrodes disposed on a vibratingplate provided at a head-end of the probe, according to one possibleconfiguration of an apparatus according to the invention;

FIG. 4A shows a train of square-wave pulses that are input to the pulsegenerator of FIG. 4;

FIG. 4B shows a train of exponential pulses that are output from thepulse generator of FIG. 4;

FIG. 5 shows one configuration of a hand-held probe that is used toprovide both electrical and mechanical stimulation to the skin,according to one or more embodiments of the invention;

FIG. 6 shows a current generator connection according to a fourthembodiment of the invention;

FIG. 7 shows elements provided at the head portion of a probe, accordingto a fifth embodiment of the invention; and

FIG. 8 shows a front view of the head portion of the probe according tothe fifth embodiment of the invention;

FIG. 9 shows a front view of the head portion of the probe according toan eighth embodiment of the invention;

FIG. 10 shows a first section view of the head portion of the probeaccording to the eighth embodiment of the invention, whereby suction isnot being applied to the skin;

FIG. 11 shows a second section view of the head portion of the probeaccording to the eighth embodiment of the invention, in which suction isbeing applied to the skin;

FIG. 12 shows a structure of an electroporation device according to aninth embodiment of the invention;

FIG. 13 shows components used to couple electrodes and wires to a headof the electroporation device according to the ninth embodiment of theinvention;

FIG. 14 shows a side view of the head of a probe used in an apparatusaccording to the ninth embodiment of the invention;

FIG. 15 shows a back view of the head of a probe, along withtransformers shown, in an apparatus according to a tenth embodiment ofthe invention;

FIG. 16 shows a front view of the head of a probe used in an apparatusaccording to the tenth embodiment of the invention;

FIG. 17 shows a front view of the head of a probe having threeelectrodes, which is used in an apparatus according to an eleventhembodiment of the invention;

FIG. 18 shows a back view of the head of a probe having threeelectrodes, along with transformers providing electronic pulses to thethree electrodes, which is used in an apparatus according to theeleventh embodiment of the invention;

FIG. 19 shows staggered square-wave input pulses and exponential outputspulses with respect to the three transformers which is used in anapparatus according to the eleventh embodiment of the invention; and

FIG. 20 shows a gauze pad provided between a probe (according to any ofthe embodiments of the invention) and a patient's skin, according to atwelfth embodiment of the invention.

FIGS. 21-24 show different views of a skin treatment device according toa thirteenth embodiment of the invention.

FIGS. 25-27 show one possible implementation of a skin treatment deviceaccording to a fourteenth embodiment of the invention.

FIGS. 28-31 show another possible implementation of a skin treatmentdevice according to the fourteenth embodiment of the invention.

FIGS. 32A, 32B and 32C show one possible implementation of a skintreatment device according to a fifteenth embodiment of the invention.

FIGS. 33A and 33B show another possible implementation of a skintreatment device according to the fifteenth embodiment of the invention.

FIGS. 34A, 34B and 34C show still another possible implementation of askin treatment device according to the fifteenth embodiment of theinvention.

FIGS. 35 and 36 still another possible implementation of a skintreatment device according to a sixteenth embodiment of the invention.

FIGS. 37-40 show still another possible implementation of a skintreatment device according to a seventeenth embodiment of the invention.

FIGS. 41-43 show still another possible implementation of a skintreatment device according to an eighteenth embodiment of the invention.

FIGS. 44 and 45 show still another possible implementation of a skintreatment device according to a nineteenth embodiment of the invention.

FIGS. 46-48 show still another possible implementation of a skintreatment device according to a twentieth and twenty-first embodiment ofthe invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Preferred embodiments of the invention will be described in detailbelow, with reference to the accompanying drawings.

Based on experimental tests on the skin, it has been found by theinventor that after one or more pulses are applied between two points onthe skin, transpiration (or absorption) in the area between the twopoints on the skin increases. The pulses that give optimal results areexponential pulses that are generated by a charged capacitor that isdischarged on at least two separate points on the skin.

These experimental results have been utilized by the inventor in orderto develop an apparatus and method that maintains the transpiration ofthe skin at a high level, so that the skin can readily absorb a gel,liquid, lotion, cream, or drug that is applied to the skin. The drug maybe used to treat skin melanoma and/or cancerous tumors located justbelow the skin surface, for example.

The apparatus according to an embodiment of the present inventionapplies a sequence of pulses over an area or skin, by using an array ofelectrodes that are placed in contact with the skin. The array ofelectrodes are provided on a vibrating plate at the head of a probe,such as a hand-held probe 500 as shown in FIG. 5. The array ofelectrodes may be a configured as shown in FIG. 2A in a firstembodiment, whereby odd rows of electrodes are electrically connected toeach other, and thereby to a first output of a pulse generator 400 (seealso FIG. 4) via a first electrical connection. The even rows ofelectrodes are electrically connected to each other, and also to asecond output of the pulse generator 400 via a second electricalconnection. The array of electrodes on the vibrating plate mayalternatively be configured as shown in FIG. 2B in a second embodiment,whereby odd rows of round electrodes are electrically connected to eachother, and thereby to the first output of the pulse generator 400 via afirst electrical connection. The even rows of round electrodes areelectrically connected to each other, and thereby to the second outputof the pulse generator 400 via a second electrical connection.

The increase of the transpiration of the skin that is obtained by way ofthe present invention has the effect of increasing the absorption ofliquids, creams, lotions, gels, or skin treatment drugs (or other kindsof drugs) that have been previously provided on the skin in the areabetween where the electrodes are applied to the skin.

The electrical pulses that are applied on the skin in order to enhancethe transpiration of the skin are pulses obtained by a discharge of acapacitor on the skin. That is, the skin acts as a capacitive load whena probe is applied to the skin. A square-wave pulse input to a primarywinding of the transformer 410 of FIG. 4, with an output of thesecondary winding of the transformer 410 being coupled to the skin byway of the electrodes, provides the same effect as a dischargingcapacitor. However, by using a transformer 410 instead of a capacitor,one can obtain current control with respect to electrical pulses appliedto the skin, so that the amount of current applied to the skin duringtreatment of the skin does not exceed a predetermined maximum currentvalue.

The exponential pulses are generated during the rising edge and fallingedge of each square-wave input pulse that is input to the transformer410 from a square-wave pulse generator, and have opposite sign (positiveexponential pulse due to the rising edge of a square-wave input pulse,negative exponential pulse due to the falling edge of the samesquare-wave input pulse). With the use of such a pulse generator 400 asshown in FIG. 4, it is possible to apply a burst of separate pulses(e.g., 500 to 1500 per second) to the skin, with adjacent pulses beingof opposite polarity and which provides a transpiration effect betterthan just providing one pulse or many pulses of the same polarity to theskin.

Also, by outputting bursts of pulses to the skin in which each burst ofpulses includes adjacent pulses in the same burst of opposite polarity(e.g., +−+−+−+−+− . . . ), any potential current buildup in the skin isobviated due to the cancellation effect cause by utilizing adjacentpulses of opposite polarity. This is in contrast to the conventionaldevices that output electrical pulses of the same polarity, which mayresult in current buildup in a patient's skin, which may lead todamaging effects caused to the skin as a result of the current buildup.

As explained above, a burst pulse generator utilizes an inductiveelement (e.g., a transformer) instead of a capacitor, so that thecurrent-to-be-applied to a patient's skin can be controlled. Inconventional devices that utilize a capacitor for their electrical pulsegenerator, when that capacitor is coupled to a patient's skin, theresultant circuit amounts to a first capacitor (that being the capacitorof the pulse generator) in parallel with a second capacitor (that beingthe capacitor due to the capacitive/resistive effect of a skin operatingas a load). When a voltage is applied to the skin by way of anelectrical pulse, the discharge of a voltage from the first capacitor tothe second capacitor results in a very large current spike for aninitial short period of time, whereby that large current spike cannot bereadily controlled. This can result in negative effects to the patient'sskin caused by the large current spike. By utilizing an inductiveelement (e.g., a transformer) instead of a capacitive element in thepulse generator, as shown in FIG. 4 of the drawings, no current spikeresults when a probe with electrodes providing electrical pulses iscoupled to a patient's skin (since the “capacitive skin” smoothlyreceives the current and voltage from the “inductive pulse generator”).

Switching transistor 430 provides square-wave pulses as shown in FIG. 4Ato the primary winding of the transformer 410, as shown in FIG. 4. Thepulses generated by the pulse generator 400 of FIG. 4, when the load isa pure resistance (or inductive or other type of reactive load), is asequence of exponential decay pulses of opposite symmetrical polarities,as shown in FIG. 4B. Such a circuit that includes the pulse generator400 provides an excellent coupling to the impedance of the skin.Moreover, in addition to the current control described above, theinductance of the transformer 410 together with the capacitance of theskin generates a resonant circuit, which is desirable to achieve anopening of the skin pores or membranes.

The voltage waveform is conveniently modified when applied to the skindue to the fact that the electrical equivalent circuit of the skin is aresistance and a capacitance in parallel. The resulting voltage waveformhas a longer rise time (due to the RC time constant), and is dependentupon the capacitance of the skin, while maintaining the same peakcurrent and the same exponential decay waveform.

Such a circuit according to the first embodiment gives an advantage incomparison to traditional pulse generators that deliver pulses of apredefined value and shape of tension or current. By way of the presentinvention according to the first embodiment, it is possible to deliverhigher energy value per pulse, and also at the same time avoid possibledamage to the skin that would occur if high current amounts were appliedto the skin. The circuit utilized in the first embodiment self adjuststhe value of the current, voltage and waveform shape. In particular, theimpedance of the skin decreases after the first pulse is applied to theskin. In this way, the voltage of the first pulse is higher thansubsequent pulses, since the impedance of the skin is higher at the timethe first pulse is applied to the skin. The voltage of the second andfollowing pulses applied to the skin decreases with the decreasing ofthe impedance of the skin, while maintaining the peak current at thesame or almost the same value.

Typical values of current and voltage are provided herein. Case 1: loadimpedance of 10 kohm, peak voltage of 100 V, peak current of 10milliamperes, pulse width of 220 microseconds. Case 2: load impedance of1 kohm, peak voltage of 10 V, peak current of 10 milliamperes, pulsewidth of 220 microseconds. The pulses are preferably delivered inbursts, where the burst rate is the same or nearly the same as themechanical vibration rate. A typical value of the burst rate (andmechanical rate) is between 40 Hz and 100 Hz.

The inventor of this application has also realized that the use ofmechanical vibrations at the same time that the electrical pulses areapplied to skin, and at a same or nearly the same frequency as the burstpulse rate, results in a patient having a greater tolerance to thestrength (current and voltage) of the electrical pulses applied to thepatient's skin. For example, using a electrical pulse burst rate of 50Hz (that is the rate between bursts of pulses), mechanical vibrationsmay be provided at a range of between 40 to 60 Hz at the same time thatthe electrical pulse bursts are applied to the skin, to provide a“masking effect.” The inventor has also found that utilizing mechanicalvibrations at or around (e.g., +/−10% of) the fundamental frequency ofthe electrical pulse burst rate, at or around the first harmonic of theelectrical pulse burst rate, at or around the second harmonic of theelectrical pulse burst rate, and/or at or around the third harmonic ofthe electrical pulse burst rate, gives the patient a “good sensation” sothat he/she can tolerate a higher strength of electrical pulses beingapplied to his/her skin at the same time. Thus, for a 50 Hz electricalpulse burst rate, mechanical vibrations may be applied to the patient'sskin at the same time, with the mechanical vibration rate being either40 to 60 Hz, 90 to 110 Hz, 140 to 160 Hz, and/or 190 to 210 Hz. Byhaving mechanical vibrations applied to the patient's skin at the sametime that the electrical pulse bursts are applied to patient's skin, thepatient's discomfort level caused by the tingling sensation of theelectrical pulses is lessened (e.g., masked somewhat).

Normally, when a square wave is applied to the skin, due to thecapacitive effect of the skin, it is possible to obtain about a threemicrosecond time constant exponential decay current. This is whathappens when a square wave voltage is applied to a circuit thatcorresponds to a resistor in parallel with a capacitor.

With such a circuit, only the peak current is enhanced, charging to amaximum allowable voltage the skin capacitance by applying an electricalenergy equal to the magnetic energy of the transformer 410. This effectmost likely provides for the opening of the cell membranes or pores ofthe skin (to achieve the transpiration effect) only during the time wheneach pulse is applied to the skin.

The effect of applying the probe to the skin is that the skin vibratesdue to the electrical pulses applied by way of the array of electrodes.The electrical pulses are preferably applied at a fixed frequencybetween 200 and 10,000 Hz (optimally at a frequency value between 2,500to 3,000 Hz), and are grouped in burst of pulses (e.g., each burst maycorrespond to 100 to 1000 separate pulses that have opposite polaritieswith respect to adjacent pulses in the same burst of pulses). The ONtime of each burst is a fixed value between 5 to 50 milliseconds, andthe OFF time between two consecutive bursts is a fixed value between 5to 50 milliseconds (the preferred burst ON time is 10 milliseconds andthe preferred OFF time between consecutive bursts is 10 milliseconds).

As described above, the electrical pulses applied to the skin by way ofthe electrodes are preferably exponential pulses with peak-to-peakvoltage of 160 V at a fixed frequency between 2,500 to 3,000 Hz. One wayof providing such electrical pulses is by an electrical structure thatcorresponds to a pulse generator 400 as shown in FIG. 4, in which atransformer 410 is used as an element of the pulse generator 400.

The transformer 410, as well as the other elements of the pulsegenerator 400, are preferably housed within the probe 500 of FIG. 5.

Referring back to FIG. 4, the primary winding 420 of the transformer 410is driven by a transistor 430 that is switched on and off, and thesecondary winding 440 of the transformer 410 is directly applied to thearray of electrodes (see FIG. 1A or 1B) with an electrical resistance450 provided therebetween. The electrical resistance 450 may be 200 Kohmor some value in that range (e.g., 100 Kohm to 500 Kohm), and isprovided in order to avoid high voltages when the array of electrodesare not applied to the skin, so that in that case it operates as an opencircuit. In such a situation, the peak-to-peak voltage is 400 V orthereabouts.

Along with the electrical pulses applied to the skin, a mechanicalvibration is also provided to the skin in the first embodiment in orderto increase the absorption of a substance that is applied on the skin.

The absorption effect is enhanced by the simultaneous increase oftranspiration, whereby the absorption effect is greatest when themechanical vibration is synchronized in phase and in frequency with theelectric pulse application. Thus, in the example discussed above, whilethe electrical burst of pulses (at 2,200 Hz) are provided to the skin ata burst ON/OFF frequency, e.g., 50 Hz, by way of an electrode array, theskin is also mechanically vibrated at the same frequency, e.g., 50 Hz,by way of the vibrating plate. The mechanical vibration and theelectrical burst application are also preferably provided in phase withrespect to each other, in order to increase the skin absorption effect.There are several well known ways to achieve this frequency and phasesynchronization. In the preferred embodiments described herein, anoptical sensor (not shown) detects the movement of the eccentric of amotor that is used to provide the mechanical vibrations (see FIGS. 1Aand 1B, for example), and gates the burst of electrical pulses based onthe detected movement.

Thus, in the example discussed above, while the burst of electricalpulses are provided to the skin by way of the electrode array, the skinis also mechanically vibrated at the same frequency by way of thevibrating plate. The mechanical vibration and electrical pulseapplication is also preferably provided in phase with respect to eachother, in order to increase the skin absorption effect.

Moreover, the absorption effect is further enhanced when the mechanicalvibration is applied orthogonal to the surface of the skin. WhileApplicant does not intend to be tied down to any particular theory ofoperation, one possible explanation of the physical phenomena of one ormore embodiments of the present invention is that, while the electricalpulses “stretch” the skin, thus increasing periodically the diameter ofthe pores of the skin, at the same time the mechanical vibration “pumps”the substances (gel, liquid or cream) inside the skin (through theopened pores). The mechanical and electrical synchronization achievesthe effect that the “pumping” action (due to the mechanical stimulationof the skin) takes place at the same instant in time that the pores areat their maximum “open” diameter (due to the electrical stimulation ofthe skin).

The apparatus according to a first embodiment the present inventionincludes a probe having two main parts:

A) a handle containing a power source (e.g., batteries) and a pulsegenerator; and

B) a vibrating head containing components for generating the vibrationand also containing an array of electrodes.

The vibrating head, in a preferred configuration of the firstembodiment, includes a D.C. electrical motor for generating vibrationsto the skin. FIGS. 1A and 1B show two different views of the D.C.electrical motor 110, the rotating shaft of the D.C. electrical motor110 is an eccentric 120 to thereby provide eccentric motion. Theeccentric motion, during rotation of the D.C. electrical motor 110,generates a vibration onto the vibrating plate 130 (that is directlycoupled to the D.C. electrical motor 110) that is at the same frequencyof the rotation of the D.C. electrical motor 110 (e.g., 50 Hz or 60 Hzor some other desired frequency). Other ways of causing vibrations insynchronization with the providing of electrical pulses to a patient maybe contemplated while remaining within the scope of the invention. Notethat the use of mechanical pulses at the same or nearly the same rate asbursts of electrical pulses, but not necessarily in synchronism witheach other, as described earlier, provides a good effect in that itlessens the patient's discomfort level associated with the buzzing andtingling sensation caused by receiving electrical pulses to the skinalone. Also, the use of adjacent pulses in each burst of oppositepolarity to each other results in no current buildup to the patient'sskin, which can be a detrimental effect of conventional devices that useelectrical pulses of the same polarity to be provided to a patient'sskin.

As explained earlier, FIG. 4 shows circuitry for providing electricalpulses to the array of electrodes shown in FIGS. 2A and 2B. Thecircuitry of FIG. 4 corresponds to a pulse generator 400, and ispreferably disposed within the housing of the probe 500 of FIG. 5. Theelectrical pulses generated by the pulse generator 400, when thosepulses are provided to the skin, preferably are exponential pulses withpeak-to-peak voltage of 160 V at a frequency of between 2,500 Hz to3,000 Hz. Of course, other peak-to-peak voltage values (e.g., 100 V to200 V) and operating frequencies (50 Hz to 15,000 Hz) may be employed,while remaining within the scope of the invention as described herein.Alternatively, sawtooth or sinusoidal pulses may be provided to theelectrodes, but exponential pulses appear to provide better skintranspiration results.

FIGS. 1A and 1B show the vibrating plate 130 that is physically coupledto the D.C. electrical motor 110. The vibrating plate 130 preferably is50×50 mm in size (other sizes are possible while remaining within thescope of the invention), where parallel metallic stripes are depositedon it as shown in FIG. 2A, in order form the array of electrodes. Thevibrating plate 130 is caused to vibrate at the same phase and frequencyas the electrical pulses provided to the skin by way of the array ofelectrodes (disposed on the vibrating plate), in order to enhance theskin absorption effect.

As shown in FIG. 2A, which shows a first embodiment of an electrodearray 210 that is provided on a skin-side surface of the vibrating plate130, five parallel metallic stripes 220 are provided, each preferably ofa size of 50 mm×4 mm. Each of the five electrodes 220 are preferably 6mm apart from adjacently-positioned electrodes. The electrodes 220 arealternately electrically connected (e.g., the first, third and fifth roware electrically connected to each other by way of electrical line 250;and the second and fourth rows are electrically connected to each otherby way of electrical line 260). Other electrode array configurations arepossible while remaining within the scope of the invention, such havinga number of electrodes greater than two, such as having seven or eightelectrodes.

FIG. 2B shows a second embodiment of an electrode array that is providedon a skin-side surface of a vibration plate. In FIG. 2B, there areprovided 25 round electrodes 230 each of 4 mm diameter, each separatedat least 6 mm from adjacently-positioned round electrodes. The roundelectrodes 230 are alternately electrically connected to each other(e.g., the electrodes on the first, third and fifth rows areelectrically connected to each other by way of electrical line 270; andthe electrodes on the second and fourth rows are electrically connectedto each other by way of electrical line 280). The spacing between theelectrodes 230 shown in FIG. 2B may vary between 1 to 20 mm and the sizeof each of the electrodes 230 may vary between 1 to 20 mm in diameter.

FIG. 2C shows an array of electrodes provided on an outer surface of thevibration plate that faces the skin, according to the third embodimentof the invention. In FIG. 2C, there are provided electrodes 233 that aredisposed on the periphery of the vibration plate, which are electricallycoupled to each other, and which are electrically coupled to a firstoutput of the pulse generator 400 by way of a first electricalconnection 235. In FIG. 2C, there is also provided acentrally-positioned electrode 237, which is not electrically coupled toany other of the electrodes, and which is electrically coupled to asecond output of the pulse generator 400 by way of a second electricalconnection 239.

FIG. 3 shows a side view of a vibrating head 310 of a probe that is usedto provide both electrical and mechanical stimulation to the skinaccording to an embodiment of the present invention, in order to have asubstance previously applied to the skin be absorbed better. As shown inFIG. 3, the vibrating head 310 includes the array of electrodes 320provided on a skin-side surface thereof. The array of electrodes 320 maybe provided in a manner such as shown in either FIG. 2A or 2B, forexample. Between the array of electrodes 320 and the skin 330 there isprovided a substance 340 to be absorbed, whereby the substance 340 hasbeen previously applied to the skin 330 (e.g., applied to the skinbetween 30 seconds to 2 minutes before the probe is to be applied to theskin 330). Application of mechanical vibrations and electrical pulsesenhances the absorption of the substance 340 into the skin 330.

FIG. 5 shows one configuration of a hand-held probe 500 that may be usedto provide both electrical and mechanical stimulation to the skin,according to one or more embodiments of the invention. The probe 500 isconfigured to be readily held by one hand of a user. A bottom portion ofthe probe 500, at which a user's hand is gripped thereon to thereby holdthe probe 500, may include an outlet 510 for coupling an electricalcable to an electrical outlet (e.g., wall outlet), so as to provide A.C.voltage to the probe 500 in that manner. Alternatively, battery powermay be used, by way of batteries (not shown) disposed within the housingof the probe 500. Battery power may be utilized when A.C. power is notreadily available. Also, the pulse generator 400 of FIG. 4 is preferablyhoused at the handle portion of the probe 500.

The head portion of the probe 500 is where the vibrating plate 130 (seeFIG. 1A or 1B) is provided, and also where the D.C. electrical motor 110(see also FIG. 1A or 1B) that provides the mechanical vibrations to thevibrating plate 130 is preferably provided housed within. The array ofelectrodes (see FIG. 2A or 2B) are provided on an outer surface of thevibrating plate 130, thereby facing the skin of a user to be treatedwith the probe 500.

A typical application time of the probe to the skin may be on the orderto 10 s of seconds up to several minutes.

In a fourth embodiment, as shown in FIG. 6, the output of the pulsegenerator 400 (see also FIG. 4) is connected to a D.C. current generator610, which induces a iontophoresis effect in addition to the previouslydescribed skin absorption/transpiration effects. The iontophoresiseffect is well known to those skilled in the art, and severaliontophoresis electrical generators are currently available in themarket, either D.C. or D.C. pulsed. A D.C. current output by the D.C.current generator 610 is applied between the electrodes of the probe anda ground plate that is connected with the patient's body. Depending onthe substance to be absorbed into the patient's skin, the patient groundplate connection is coupled to either the positive or the negative ofthe D.C. current generator 610, in a manner known to those skilled inthe art. Instead of using continuous D.C. current, there canalternatively be provided D.C. current pulses that have the same averagecurrent value as the continuous D.C. current case, and which have a dutycycle between 5 and 50% and a frequency between 10 and 5000 Hz. In sucha case, the peak current of the D.C. current pulses is higher during thepulsed (ON) times.

In a fifth embodiment, as shown in FIGS. 7 and 8, a dispenser or chamber710, which is configured to hold liquid or cream or gel 720, isintegrated in the vibrating head of the probe. The dispenser or chamber710 is provided between an array of electrodes 705 and the vibratingplate 130. The burst of electrical pulses are applied by way of aconductive roller 740 that dispenses the liquid, and by the array ofelectrodes 705. A D.C. current as in the third embodiment can also beadded between the array of electrodes 705 and the patient's body, toinduce a iontophoresis effect as well. While the vibrating head is movedon the patient's skin, the roller 740 delivers the liquid or cream orgel 720 to the patient's skin.

The chamber 710 in which the roller 740 is disposed in the vibratinghead can be filled with a liquid, cream or gel substance 720 by way of aremovable cap (not shown). In particular, the cap is removed (e.g.,screwed off of the head of the probe), and then a user fills the chamber710, through the liquid inlet 760, with the substance 720 to be providedto the patient's skin. The user then closes the cap (e.g., screws itback onto the liquid inlet 760) to thereby keep the substance 720 withinthe chamber 710 of the probe until it is ready to be applied to thepatient's skin by way of the roller 740.

FIG. 8 shows a front view of the electrodes 705, which are shown as twostripe electrodes that are electrically connected to each other by wayof electrical connection 820. Of course, other types of electrodearrays, such as those shown in FIGS. 2A and 2B, can alternatively beused in this fifth embodiment. The exposed surface 830 of the roller 740that applies the substance to the patient's skin, is shown in FIG. 8.Dispensing gaps 840 are also shown in FIG. 8, whereby these gaps 840allow the liquid, cream or gel substance 720 in the chamber 710 togradually come out of the chamber 710 and thereby be applied to thepatient's skin by way of the roller 740.

In a sixth embodiment of the invention, an apparatus for enhancingabsorption of the skin includes an array of electrodes, and a pulsegenerator that is electrically coupled to the array of electrodes. Thedisposition of the array of electrodes may be any of the dispositionsshown in FIGS. 2A-2C, for example. In a preferred implementation of thesixth embodiment, electrical pulses outputted by the pulse generator 400to the array of electrodes are a sequence of exponential pulses, such asthe pulse train shown in FIG. 4B. The exponential electrical pulses areapplied to the skin by way of the array of electrodes and are generatedby the secondary winding of a high voltage transformer with the primarywinding driven by a square wave voltage, as seen by FIGS. 4, 4A and 4B.

In the sixth embodiment, unlike the previous embodiments, a vibratinghead is not utilized, but rather skin absorption enhancement is obtainedjust by the providing of the electrical pulses to the skin by way of thearray of electrodes. The array of electrodes according to the sixthembodiment are provided on a plate at the head of the probe, whereby thehead and the plate do not vibrate. Thus, in the sixth embodiment, thestructure as shown in FIGS. 1A and 1B would not be utilized, but ratherjust a plate for holding the electrodes in place at the head of theprobe would be needed.

In a seventh embodiment, a vibrating head is utilized, as in the firstthrough fifth embodiments, but where the vibrating head is capable ofbeing turned on or off, by way of a control (e.g., switch) provided onthe probe. The control can readily be manipulated by an operator of theprobe, in order to treat a patient.

An eighth embodiment of the invention is described below, with referenceto FIGS. 9-11. FIG. 9 shows a front view of a head 800 of a probe,whereby that view shows the portion of the probe that is applied to theskin of a patient. FIG. 10 shows a section view taken along an axis ofone belt, and FIG. 11 shows a section view taken at the middle of thehead of the probe.

The eighth embodiment provides for a fairly even absorption under theskin of a substance previously applied to the skin, such as collagenpreviously applied to the skin. In the eighth embodiment, a head 800 ofa probe to be applied to the skin includes a vibrating plate 810, avacuum chamber 820, rollers 830, and belts 840 disposed around therollers 830. The rollers 830 are conductive rollers, whereby the rollers830 are electrically coupled to electrodes (see FIGS. 2A through 2C, forexample) provided on the vibrating plate 810. As in the otherembodiments, a pulse generator (see FIG. 4, for example) is electricallycoupled to the electrodes on the vibrating plate 810, in order toprovide electrical pulses to the patient's skin (by way of theconductive rollers).

In the eighth embodiment, the rollers 830 are separated from each otherby around 40 mm. Of course, other separation distances are possible,while remaining within the scope of the invention (e.g., 20 mm to 80 mmseparation). The rollers 830 are disposed at one end of the vacuumchamber 820, whereby the vacuum chamber 820 includes an opening that iscoupled to a pipe 845 that is in turn coupled to a vacuum pump 855.

When the vacuum pump 855 is operated, the vacuum chamber 820 generates asuction effect on the skin 850, thereby enabling a stronger contactbetween the rollers 830 and the skin 850, and thereby generating anadditional massaging effect to the skin 850, in addition to thevibrations generated by the vibrating plate 810. On opposite ends of therollers 830 are the belts 840, which are preferably rubber belts. Thebelts 840 are used in order to avoid direct friction between the skin850 and the body of the vacuum chamber 820.

The eighth embodiment provides good skin absorption results anddecreases the appearance of cellulite on the skin after application of asubstance for reducing cellulite is applied to the skin. Such asubstance for reducing cellulite that can be applied to the skin may bejarulon acid, for example. Such a substance could also be previouslyspread on the skin and absorbed by the skin utilizing one of thepreviously-described embodiments.

Also, while the eighth embodiment has been described as having avibrating plate, as in the first through fifth embodiments, anon-vibrating plate as in the sixth and seventh embodiments (when thevibrating plate is turned off) may be utilized in an alternativeconfiguration. In that case, the plate disposed above the vacuum chamberis non-vibrating, and contains electrodes disposed therein.

A ninth embodiment of the invention will be described in detailhereinbelow with reference to FIGS. 12-14. The ninth embodiment includesa motor 1, a screw 2, a slide 3, a frame 4, a piston 5, a syringe 6, apipe (or tubing) 7, a central electrode 8, and circumferentialelectrodes 9 (that are disposed outside of the central electrode 8) on ahead 10. The head 10 is a head portion of a probe, such a probe shown inFIG. 5 in the previous embodiments (except for the fifth embodiment,whereby the substance is disposed within a chamber within the head thatis adjacent to the electrode plate, and thus a syringe would not beneeded in that case), for example.

In the ninth embodiment, the syringe 6 is preferably a disposable,single-use syringe, which is positioned adjacent to the probe (only thehead 10 of the probe is shown in FIG. 12, whereby the rest of the probeis hidden behind the head 10 in the view provided in FIG. 12). Thesyringe 6 is inserted or fitted onto the frame 4, and does not moverelative to the frame 4. For example, the frame 4 may be placed on atable next to a bed on which a patient to be treated is located.

The piston 5 is operable to move relative to the frame 4, whereby themovement is caused by the motor 1, the screw 2, and the slide 3, whichoperate together as a moving means. With the configuration shown in FIG.12, the probe is free-standing and can be moved a certain amount (e.g.,1 to 10 feet, depending on the length of the tube 7) relative to theframe 4 (while maintaining a coupling to the syringe 6 by way of thetube 7 that couples the syringe 6 with the head 10 of the probe). Thatway, the probe can be moved around to treat different areas of a skin ofa patient lying on a bed, while the frame containing the syringe 6 restsin place on a table next to the bed. In an alternative configuration,the probe and the syringe 6 can both be mounted on the frame 4, as asingle-block construction. In this configuration, the entire frame ismoved to different areas of the patient's skin, to thereby treat thepatient by way of a probe that is inserted in the frame. The head of theprobe extends out from one end of the frame, so that it can be placedagainst the patient's skin.

In a preferred implementation, the motor 1 is powered by a differentpower source than the source providing power to the probe. However, in adifferent implementation, the motor 1 and the probe may be powered bythe same power source.

A tube or pipe 7 is used to connect the syringe 6 with the head 10 ofthe probe. The tube 7 is preferably a disposable, single-use component,and may be a flexible plastic tubing, for example. The head 10 ispreferably a vibrating head, such as described earlier with respect toother embodiments. In an alternative configuration, the head 10 does notvibrate, and only electrical pulses are provided to the skin (so as toelectroporate the skin to thereby absorb the substance provided to theskin by way of the syringe 6 and tube 7) in this alternativeconfiguration. The tube 7 is preferably 0.5 to 3 millimeters indiameter, and is sized so as to allow a liquid or cream-like substanceto flow through the tube 7, and exit the tube 7 at a second end oppositea first end of the tube 7 that is coupled to the syringe 6. Such asubstance to be applied to the skin may include water-based collagen,water-based elastine, and anesthetic, or other type of drug, just toname a few.

Referring now to FIG. 14, the tube 7 couples to the head 10 by way of agroove 12 that is located at an end of the head 10 and that is providedall the way to a groove 11 that surrounds the central electrode 8. Thegroove 12 is sized so as to accept the tube 7 fitted therein to providea snug fit, whereby the tube 7 is preferably fitted within the groove 12by feeding the tube 7 within the groove 12 from the end of the head 10where one end of the groove 12 is disposed. In the ninth embodiment, thesize of the groove 12 is such that the tube 7 does not extend above theupper surface of the head 10 (where the electrodes 8, 9 are disposed),or whereby the tube 7 extends slightly below the upper surface (plate)of the head 10. That way, the tube 7 will not be felt by the patientwhen the head 10 of the probe is moved along the skin of the patientduring a treatment. Preferably, the tube 7 will not be in contact withthe skin of the patient during treatment of the patient by way of amethod and/or apparatus according to the ninth embodiment. The topsurface of the head 10 preferably has a plate-like configuration, so asto provide a smooth feeling to the patient's skin.

On the top surface of the head 10 there are provided one centralelectrode 8 and a plurality of circumferential electrodes 9 disposedaround the central electrode 8. The groove or trough 11 surrounding thecentral electrode 8 is preferably 1 mm wide, whereby the groove 11 iscoupled to one end of the groove 12 in which a portion of the tube 7 isdisposed. That way, when a substance is flowed out of the syringe 6 (byway of action by the motor 1, the screw 2 and the slide 3), thesubstance flows through the tube 7 (disposed within the groove 12) andthereby into the groove 11. The substance collects within the groove 11surrounding the central electrode 8, and is absorbed by the skin duringan electroporation treatment (using electrical pulses and mechanicalvibrations) by way of the ninth embodiment. When the top surface (plate)of the head 10 is placed in contact with the patient's skin, thesubstance within the groove 11 comes into contact with the patient'sskin, and is absorbed by the skin.

Although eight circumferential electrodes 9 are shown in FIG. 12, theinvention according to the ninth embodiment can operate with differentnumbers of circumferential electrodes 9. For example, a minimum of twocircumferential electrodes 9, disposed opposite from each other (withthe central electrode 8 disposed therebetween), may be utilized in adifferent configuration. Also, four circumferential electrodes 9 andmore than eight circumferential electrodes 9 may be utilized in otherdifferent configurations (e.g., 16 electrodes, 32 electrodes, or an oddnumber, such as three, five, or seven, circumferential electrodessurrounding the central electrode 8) of the ninth embodiment.

A pulse generator, such as the one shown in FIG. 4 (see also FIGS. 4Aand 4B), is used to provide electrical pulses to the electrodes 8, 9disposed on the head 10 of the probe. As explained earlier, thepreferred shape of the electrical pulses is an exponential shape, asshown in FIG. 4B. Alternatively, sinusoidal or sawtooth waveforms may beprovided, but exponential pulses provide a better skin transpirationeffect. Operation of the pulse generator that may be utilized in theninth embodiment has been described in detail with respect to the firstembodiment described previously, and will not be described here for sakeof brevity.

One of the two outputs of the pulse generator (see FIG. 4) is connectedto the central electrode 8, and the other of the two outputs of thepulse generator is connected to one of the circumferential electrodes 9.The circumferential electrodes 9 are coupled to each other electricallyon the back side of the head (see dashed line in FIG. 2C), so that eachof the electrical pulses provided on the other of the two outputs of thepulse generator is provided to all of the circumferential electrodes 9simultaneously.

The voltage of the electrical pulses provided to the skin from each ofthe eight circumferential electrodes 9 can be considered as a “ground”with respect to the voltage of the electrical pulse provided to the skinfrom the one central electrode 8. Since the central electrode 8 carriesmore electrical current than each of the eight circumferentialelectrodes 9, the circumferential electrodes 9 act like a groundconnection, whereby the electrical current carried by each of the eightcircumferential electrodes 9 is approximately eight times less than theelectrical current carried by the central electrode 8.

The piston 5 of the syringe 6 is moved by the motor 1, which is a DCelectric motor in a preferred implementation. The motor 1 is connectedto the screw 2, which moves the piston 5 by way of the slide 3 that isattached to the screw 2 at a particular location on the screw 2. Whenthe head 10 of the probe is positioned on a patient's skin, electricalpulses are delivered to the electrodes 8, 9, and the piston 5 of thesyringe 6 is moved by the motor 1 in order to deliver the liquid orcream-like substance (or drug) from within the syringe 6 to thepatient's skin. The liquid, cream or drug is preferably provided to thepatient's skin in a slow, controlled manner, to allow the substance tobe properly absorbed within the skin. For example, a water-basedcollagen, a water-based elastine, an anesthetic, or other type of drugmay be provided within the syringe 6, to then be provided to the skin ofa patient (to be absorbed therein) by way of the method and apparatusaccording to the ninth embodiment.

The enhancement of the skin absorption by electrical pulses applied tothe skin, and also by mechanical vibrations applied to the skin at thesame time in a synchronous manner (see description of the vibratingplate with respect to other embodiments) of the ninth embodiment,enables the absorption of a drug or other type of substance delivered byway of the syringe 6. A typical drug absorption quantity is 1 cubiccentimeter in one to five minutes, by using the method and apparatusaccording to the ninth embodiment. In this regard, the timing of themovement of the piston 5 is such that the correct amount of substance isoutput from the syringe 6 during a treatment of a patient, whereby whenthe probe is turned on, this event will provide a trigger signal to themotor 1 to start to operate. Operation of the motor 1 will in turn causethe substance within the syringe 6 to be pushed out of the syringe 6,and into the groove 12 surrounding the central electrode 8.

The substance is introduced within the syringe at a previous time, sothat the syringe 6 with the substance provided therein can then beattached to the frame 4, coupled to the tube 7, and thereby provide anapparatus that can introduce drugs and/or other substances to the skinof a patient, by way of a probe having a head 10 with electrodes 8, 9provided on an outer surface or plate of the head 10. As explainedearlier, the head 10 vibrates, so that both electrical and mechanicalvibrations are provided to the patient's skin at a same time the drug orother substance is provided to the patient's skin (by way of thesubstance disposed within the trough or groove 12 being in contact withthe patient's skin during a treatment of the patient). In an alternativeconfiguration, which provides a skin transpiration effect not as good asusing both mechanical vibrations and electrical pulses, only electricalpulses are provided to a patient's skin (the head does not vibrate).This configuration is cheaper to build, and may be suitable for certaininstances.

The motor 1, screw 2, slide 3, piston 5, syringe 6, frame 4 and tube 7may be coupled to different types of probes, in order to provide anapparatus for skin absorption enhancement and transdermal drug delivery.For example, any of the probes described with respect to the otherembodiments (except those that have the substance stored in a containerwithin the head of the probe) may be utilized with the componentsdescribed above. Also, the structure for moving a substance out of thesyringe 6 may be accomplished by ways other than the screw/slide/motor“moving means” described with respect to FIG. 12, while remaining withinthe scope of the invention.

FIG. 13 shows a back view of the head 10, whereby components used tocouple the electrodes 8, 9 to the head and to provide an electricalconnection to the electrodes 8, 9 are also shown in FIG. 13. A motor1310, which includes an eccentric 1320 coupled to an output of the motor1310, is used to provide mechanical vibrations to the head 10, so thatthe apparatus provides both electrical and mechanical vibrations to apatient's skin at the same time. These mechanical vibrations arepreferable synchronized with the electrical pulses, as described earlierwith respect to other-described embodiments of the invention.

The electrodes 8, 9 are preferably screwed onto the front plate of thehead 10. Washers 1330 and screws 1340 are utilized to electricallycouple wires 1350, 1355 to the electrodes 8, 9. In particular, wire 1350(that has one end coupled to one of the two outputs of the pulsegenerator as shown in FIG. 4, for example) is electrically connected tothe central electrode 9, and wire 1355 (that has one end coupled to theother of the two outputs of the pulse generator as shown in FIG. 4, forexample) is electrically connected to the circumferential electrodes 8.Resistor 1365 is provided between the wires 1350, 1355, in the preferredconstruction. Also shown in FIG. 13 is a housing 1375 which is coupledto the head 10 by way of screws 1380. The eccentric 1320 moves withinthe housing 1375, thereby causing vibrations that are translated to thehead 10 of the probe.

A tenth embodiment of the invention will be described herein withrespect to FIGS. 15 and 16. The tenth embodiment is similar to the ninthembodiment, but utilizes a different configuration for the head, as wellas providing a plurality of transformers (see FIGS. 4, 4A and 4B). FIG.15 shows a back view of the electrodes 1500 disposed on a head 1510 of aprobe, and FIG. 16 shows a front (skin-side) view of the electrodes1500, whereby each electrode has a groove or trough 1530 surrounding it.Each groove 1530 has an outlet that extends to an edge of the head 1510,to thereby allow a respective tube 1550 to be fitted therein, so as toprovide an amount of substance from the syringe 6 to the grooves 1530.That way, the tubes 1550 do not extend above the top surface of the head1510. As an alternative to the multi-port tube configuration shown inFIG. 16, a number of syringes equal in number to the number ofelectrodes may be provided, with a tube provided to couple a syringe toan electrode.

In the tenth embodiment, each electrode 1500 is active and is connectedto its own pulse transformer 1560A-1560I. The substance from the syringe6 is provided to grooves 1530 surrounding each of the electrodes 1500.The electronic pulses are provided to each of the electrodes 1530 fromthe respective pulse transformers 1560A-1560I, whereby transformers1560C, 1560E, 1560G and 1560I provide positive pulses to theirrespective electrodes, and whereby transformers 1560A, 1560B, 1560D,1560F and 1560H provide negative pulses to their respective electrodesat the same time, for the nine electrode configuration. Moreparticularly, transformers 1560C, 1560E, 1560G and 1560I have theirprimary and secondary windings connected in phase, and transformers1560A, 1560B, 1560D, 1560F and 1560H have their primary and secondarywindings connected 180 degrees out of phase (see oppositely-positioneddots for those transformers in FIG. 15). If a square wave is applied toall of the primary windings of the transformers at the same time andwhen there is a positive transition from low to high, the transformerswith their primary and secondary windings in phase with each other willoutput a positive exponential pulse, and the transformers with theirprimary and secondary windings 180 degrees out of phase with each otherwill output a negative exponential pulse.

In the tenth embodiment, it is preferable that a first group ofelectrodes receive a positive pulse at a same time a second group ofelectrodes (equal or nearly equal in number to the first group,preferably) receive a negative pulse, to provide a good skintranspiration effect. The type of pulses, the burst duration, thefrequency, etc., are similar to the embodiments described earlier. Also,the tenth embodiment may include a mechanical vibration that is appliedto the patient's skin at the same time the electrical pulses are appliedto the patient's skin, in a manner described previously.

In an eleventh embodiment, a plurality of transformers are respectivelyprovided to output electrical pulses to a plurality of electrodesdisposed on a head portion of a probe, whereby the plurality oftransformers provide separate and independent pulse bursts to theirrespective electrodes. For example, each of the pulse generators in theeleventh embodiment may have different phase shift amounts within arange of from 0 degrees to 360 degrees. In this regard, the outputpulses from the transformers are synchronized with each other, to have aparticular out-of-phase relationship with respect to each other.

One example of an electrode array according to the eleventh embodimentis shown in FIGS. 17, 18 and 19. This example provides a three electrodeconfiguration, with no central electrode. Referring now to FIG. 17,which shows a front side of the head 10, electrodes 1700 arerespectively coupled via tube 1710 to a syringe 6, to receive asubstance in a groove 1720 surrounding each of the electrodes 1700. Likethe previously-described embodiments, as shown in FIG. 14, a groove orpath to an end of the head 10 is provided, in order to fit the tube 1710snugly within it so that the tube 1710 does not extend above the uppersurface (plate) of the head 10 that makes contact with a patient's skin.

Referring now to FIG. 18, which shows a back side of the head 10,transformers 1810A, 1810B and 1810C respective provide pulses of thesame polarity, but delayed from each other by a particular amount, tothe corresponding one of the electrodes 1700 coupled to eachtransformer. FIG. 19 shows the input square wave pulses that areprovided to each transformer, whereby the square wave pulses that areinput to transformer 1810C are delayed a certain amount (e.g., 30degrees) with respect to the square pulses that are input to transformer1810B, which in turn are delayed a certain amount (e.g., 30 degrees)with respect to the square wave pulses that are input to transformer1810A. This can readily be done by providing the trigger “IN” signal toeach of the respective transformers 1810A, 1810B, 1810C at theappropriate timings. The result are exponential pulses that are outputfrom each of the three pulse generators, whereby the exponential pulsesare phase-shifted a fixed amount with respect to each other.

With the three-electrode and three-pulse-generator configuration asshown in FIGS. 17-19, it is possible to provide a 120 degree phase shiftwith respect to the signals output by the three pulse generators (e.g.,one signal output at 0 degrees, one signal output at 120 degrees, andone signal output at 240 degrees). This provides a rotation of theelectric field between the electrodes 1700 in a manner similar to whathappens with a rotation of a three-phase motor. More generally, in theeleventh embodiment, using a number “n” of electrodes and “n” pulsegenerators, one of ordinary skill in the art will understand that onecan devise any particular type of electric field distribution on theskin surface to be treated by way of an apparatus according to theeleventh embodiment, as desired.

A twelfth embodiment of the invention will be described below withreference to FIG. 20. In the twelfth embodiment, a probe 2010 is used toprovide a skin-absorbing substance to the skin. In that regard, theprobe 2010 may be a probe according to any of the previous embodimentsof the invention described earlier in this application. As shown in FIG.20, the probe 2010 has a vibrating head 2020 and an electrode array 2030provided at an end portion of the vibrating head 2020. In the twelfthembodiment, gauze 2033 is provided between the head 2020 of the probe2010 and the patient's skin 2040. Preferably, the gauze 2033 is a padhaving a same size (or substantially the same size) as the head 2020 ofthe probe 2010 or larger in order to cover the treatment area where thehead 2020 is supposed to be moved. In a preferred implementation, thegauze 2033 is a pad (e.g., rectangular or square shaped, with athickness between 0.1 to 1 mm) that is commercially available on themarket. With the gauze 2033 provided between the probe 2010 and thepatient's skin 2040, the probe 2010 does not come into direct contactwith the patient's skin 2040. The gauze 2033 allows for the probe 2010to be moved over the patient's skin 2040 in an easier manner and withless friction than in a case where the gauze 2033 is not utilized. Also,the inventor has found out that the use of the gauze 2033 provides for amore even application of the skin-absorbing substance 2035 to thepatient's skin 2040. As an alternative to gauze, other types of pads,such as a cotton tissue or a synthetic (e.g., nylon) tissue, may be usedbetween the patient's skin 2040 and the probe 2010. All of these padshave a characteristic of sufficient porosity to allow the skin-absorbingsubstance 2035 to pass from (its container within) the head 2020 of theprobe 2010 (for those embodiments in which the skin-absorbing substance2035 is stored within the head 2020 of the probe 2010) and through thepad 2033 and thereby onto the patient's skin 2040.

In the present invention according to the twelfth embodiment, animportant feature is that gauze is provided between the head of theprobe and the patient's skin. In one possible implementation, the gauzeis affixed to the head of the probe and not to the patient's skin. Inanother possible implementation, the gauze is affixed to the patient'sskin and not to the head of the probe. With either implementation, oneobtains a more even distribution of the skin absorbing substance to theskin (as compared to the case whereby no gauze is utilized), and at thesame time allows the head of the probe to be moved across the patient'sskin (to treat a particular region of the patient's skin) with lessfriction (as compared to the case whereby no gauze is utilized). Thegauze can be releasably affixed to the patient's skin in one possibleimplementation of the twelfth embodiment in a variety of ways, such asby using medical tape. The gauze can be releasably affixed to the headof the probe in another possible implementation of the twelfthembodiment in a variety of ways, such as by rubber-banding the gauze padto the head of the probe (with the rubber band gripped around thesidewalls of the head of the probe), or by using adhesive tape to adherethe peripheral edges of the gauze pad to the sidewalls of the head ofthe probe, or by providing a gauze pad with an outer (e.g., plastic)sheath that allows the gauze pad to be easily fitted onto and off of thehead of the probe. In any of these cases, the gauze can be readilyremoved from the patient's skin or the head of the probe, and disposedafter use.

In a thirteenth embodiment of the invention, with reference to FIGS.21-24, a skin treatment device is configured to deliver a defined amountof lidocaine, ascorbic acid, or other type of skin treatment drug intothe dermis. On the head of a probe which can be constructed as describedwith respect to the third embodiment, i.e., with a central electrode2110 and eight electrodes 2120 disposed around the central electrode,where the central electrode 2110 is connected to one output of the pulsetransformer and the eight electrodes 2120 are connected to the otheroutput of the pulse transformer, a plate 2210 is coupled to the head(see FIGS. 23 and 24), with the electrodes 2110, 2120 provided betweenthe head 2130 of the probe and the patient's skin.

The plate 2210 is preferably a plastic layer (with a thickness of 300microns in a preferred implementation), where there are drilled nineholes that correspond to the nine electrodes disposed on the head. Theplate preferably has a top surface area of 60 mm×60 mm (on which theelectrodes are disposed at different points on the top surface area). Ontop of the plastic layer 2210 are glued (other methods of adhering maybe contemplated while remaining within the scope of the invention, suchas taping) two concentric squares 2230, 2240 made of non conductiverubber. Each of the concentric squares 2230, 2240 preferably has a 5 mmwidth and a 5 mm thickness. Between the outer square 2240 and the innersquare 2230, a first (or outer) gauze pad 2260 is fitted. A second (orinner) gauze pad 2270 is fitted within the inside of the inner square2230. The outer gauze pad 2260 is thereby in contact with the eightelectrodes 2120, while the inner gauze pad 2270 is in contact with thecentral electrode 2110. The inner square 2230 provides an electricalseparation between the inner gauze pad 2270 and the outer gauze pad2260, and the outer square 2240 operates to hold the outer gauze pad2270 in place against the top surface of the plate 2210. The inner gauzepad 2270 and the outer gauze pad 2260 preferably have the samethickness, 5 mm, as the thickness of the inner square 2230 and the outersquare 2240.

In a preferred implementation of the thirteenth embodiment, the outergauze pad 2240 is soaked with around 2 ml. of fisiological solution (1%NaCl) and the inner gauze pad is soaked with 0.5 ml. of 5% lidocainecloridrate water solution. The plate 2210 is disposed between thepatient's skin and the vibrating head of the probe.

An experiment performed on a mouse demonstrated that the same amount ofradioactive lidocaine is transported in to the skin, after amicrodermabrasion treatment, by the system and method according to thethirteenth embodiment, as compared to an iontophoretic device set at thesame value of the product of the current* (“*” is a multiplicationoperator) time, where the current of the iontophoretic device is set inorder to be in a first positive phase positive and in a second negativephase and the current of the system and method according to thethirteenth embodiment is set such that the product average current perpulse per total time of the positive pulses has the same value as thepositive phase of the iontophoretic device, and the product averagecurrent per pulse per total time of the negative pulses has the samevalue as the negative phase of the iontophoretic device.

The experiment described above demonstrated the advantages of thepresent invention according to the thirteenth embodiment as compared tothe use of an iontophoretic device. One advantage of the presentinvention, thanks in part to the use of symmetrical pulsed current, isthat it does not cause a chemical reaction at the electrodes. Aniontophoretic device, on the other hand, causes electrolysis with changeof PH on the skin and thereby can result in an adverse effect on theskin (e.g., redness on the skin, inflammation on the skin, burns on theskin). The use of the present invention according to the thirteenthembodiment allows one to provide skin absorption treatment to the skinafter a microdermabrasion has been performed on the skin which removedthe stratum corneum (the outer layer of the skin that is exposed toair), whereby the use of an iontophoretic device to provide skintreatment could cause higher damage if a change of PH on the skinoccurs. This problem does not occur when the thirteenth embodiment ofthe invention is utilized instead of an iontophoretic device. The use ofthe two techniques together (dermabrasion and then skin treatment byutilizing the system or method according to the thirteenth embodiment)gives a higher flow of a skin treatment substance (about 50% increase)as demonstrated by the experiment on the mouse.

A further advantage of the present invention according to the thirteenthembodiment as compared to an iontophoretic device is that the presentinvention according to the thirteenth embodiment allows for thepossibility to use any type of ionic water-based substance as a skintreatment substance without the risk of chemical reaction at theelectrodes that could change the characteristics of the appliedsubstance and thereby cause an adverse effect on the skin. The causingof an adverse effect on the skin is a situation that could occur in aniontophoresis treatment and thereby prevents the use of many substancesto be applied to the skin. This problem does not occur when the systemor method according to the thirteenth embodiment is utilized instead.

In an alternative implementation of the thirteenth embodiment, the twogauze pads are substituted with two hydrogel pads, the outer pad with 1%NaCl and the inner pad with 5% Lidocaine Cloridrate. Besides NaCl, othertypes of solutions for the outer pad may include other water-based ionicconductive substances, or the same substance as used in the inner pad,for a larger absorption surface. Besides lidocaine cloridate, othertypes of solutions for the inner pad may include: ascorbic acid,jaluronic acid, collagen, elastin, cogic acid, salicilic acid,liposomes, anti-inflammatory steroids or local anesthetics.

In the case of this embodiment, the use of synchronous mechanicalvibrations together with a burst of pulses give a small increase ofabsorption rate, and it also gives a decrease in the sensitivity of thepatient to the pain generated by the current pulse, thereby enabling theincrease of the pulse current that is acceptable by the patient (thatis, a pulse current level that does not cause any physical discomfort tothe patient).

While the thirteenth embodiment has been described with respect to anelectrode configuration such as shown in the third embodiment describedpreviously, it may also be utilized with other types of electrodeconfigurations, whereby a first set of electrodes are covered by a firstsolution-absorbing pad such as the ones described above, and whereby asecond set of electrodes not electrically connected to the first set ofelectrodes) are covered by a second solution-absorbing pad such as theones described above.

Experimental results of the application of the several embodiments ofthe skin absorption apparatus described hereinabove to the skindemonstrated that a noticeable variation of results and rate ofabsorption of substances occurred. The analysis was carried out over anarea of skin previously dermabraded with a standard microdermabraderavailable on the market and an adjacent area not previously dermabraded.This analysis demonstrated that the results obtained in the dermabradedarea are fairly constant and reproducible while the results in thenon-dermabraded area are variable and somewhat inconsistent. Thisinconsistency is due to the fact that the stratum corneum (also referredto as the horny or dead outermost layer of the epidermis) of the skinacts like a barrier to the absorption of the substances applied to theskin, and moreover it increases the electrical resistance of the skin,thereby somewhat decreasing the absorption effect of the skin absorptiontreatment according to the invention.

The thickness of the stratum corneum is variable from person to person,and moreover it is variable from time to time in the same person. Thisinduces a variability that makes it difficult to come up with a standardapplication time of the skin absorption apparatus according to thevarious embodiments of the invention. For this reason, according to yetanother embodiment of the invention, a skin absorption treatment methodincludes a microdermabrasion performed before the application of theskin absorption apparatus in order to give more reproducible and moreconstant results as compared to the embodiments in which amicrodermabrasion is not first performed. The microdermabrasion to beperformed prior to the skin absorption treatment may be one described invarious U.S. patents assigned to Mattioli Engineering, Ltd., such asU.S. Pat. Nos. 6,322,568 and 6,039,745, each of which are incorporatedin their entirety herein by reference, or other types of dermabrasiontreatments conventionally known.

Preferably, the dermabrasion treatment is performed for three minutes inorder to remove a 100 micron layer of the stratum corneum layer of theskin in an area to be later treated with a skin absorption enhancementdevice according to one of the embodiments of the invention. Ideally,the skin absorption treatment is performed soon after (e.g., within 5minutes) of the completion of the dermabrasion treatment. Of course,other time lengths of dermabrasion treatment, depth of stratum corneumremoval, and time between the dermabrasion treatment and the skinabsorption treatment, may be contemplated while remaining within thescope of the invention as described hereinabove.

A fourteenth embodiment of the invention will now be described indetail. The fourteenth embodiment of the invention is directed to amethod and apparatus for skin absorption enhancement and cellulitereduction, and it can be used as a modification of the fifth or eighthembodiments described previously. In the fourteenth embodiment, in orderto increase the speed and efficiency of the cellulite reduction, it hasbeen determined by the inventor that a controlled heating of the skinsurface and the area beneath the skin surface having the cellulite andthe fatty tissue, causes an increase in the absorption rate of asubstance to be introduced into the skin (and thereby to the regionbeneath the skin having the cellulite and the fatty tissue). Thisresults in a faster and more efficient reduction of cellulite and fattytissue in the patient.

The heating of the skin may be effected in at least two different ways:a) a 50 W infrared heating lamp positioned between rollers positioned onthe head of the probe, or b) a radio frequency at a frequency of 13.54MHz, 50 W power, whereby the rf is provided to the skin by way of therollers positioned on the head of the probe, or c) a pulsed laser, suchas a pulsed Nd Yag laser, which provides laser energy to the skin by wayof the rollers positioned on the head of the probe.

With respect to the controlled heating of the skin, by way of exampleand not by way of limitation, the skin surface is preferably heated to atemperature of 50 degrees C., at a rate of 5 degrees C. per second. Moregenerally, the skin may be heated to a temperature of between 45 degreesC. and 60 degrees C., at a rate of between 2 degrees C. per second and40 degrees C. per second.

If heating is to be effected by way of a radio frequency, the radiofrequency is preferably a continuous wave (CW), but it may alternativelybe a wave having a particular duty cycle (e.g., between 20% and 80%). Inan alternative configuration, a temperature sensor is provided on thehead of the probe, to determine when the skin reaches the desiredtemperature. When the desired skin temperature is reached, the heatingof the skin is controlled so that the desired skin temperature ismaintained (and thus not increased). Thus, when the patient's skin isdetected to be at 50 degrees C., then the radio frequency is controlledso that it is changed from a CW signal to a pulsed signal, so that theheat applied to the skin is lessened so as to maintain the desired skintemperature during the skin treatment.

Besides using a 50 W infrared heating lamp, an LED (light emittingdiode) or laser diode or Nd Yag laser may be used instead, and also anoptical light range (e.g., 300 μm to 10 μm) may be used instead of theinfrared range. Furthermore, the power output of the lamp need notnecessary be 50 W (e.g., it can be in a range of from 25 W to 100 W).

Besides using a 13.54 MHz, 50 W radio frequency signal, a radiofrequency of between 0.5 MHz and 27 MHz may be used instead, and a poweroutput may be anywhere between 1 to 100 W. A lower radio frequencyresults in the heating of a deeper portion beneath the skin surface, anda higher radio frequency results in the heating of a shallower portionbeneath the skin surface. Thus, the particular radio frequency to usemay be dependent on the area within the patient to be treated.

Referring now to FIGS. 25, 26 and 27, one possible implementation of thefourteenth embodiment is shown. Infrared light emitting diodes (LEDs)2510 are provided on a head of a probe, whereby the LEDs 2510 arepositioned on a skin-facing surface of the vibrating plate 810. When theskin is sucked into the probe head by way of the vacuum chamber 820 andthe vacuum pump 855, the skin 850 is heated by way of the LEDs 2510,thereby causing a heating (solubilizing) of the cellulite/fat tissuebeneath the skin surface. When a substance is applied to the skin by wayof the probe, that substance can readily attach to the heatedcellulite/fat tissue, whereby the cellulite/fat tissue can be moreeasily metabolized by the patient, to thereby lose the cellulite andfat. Also shown in FIGS. 25, 26 and 27 is a rubber belt 840 that iscoupled around the rollers 830.

Referring now to FIGS. 28, 29, 30 and 31, another possibleimplementation of the fourteenth embodiment is shown. In FIGS. 28, 29and 30, the rollers are conductive rollers 830′ that provide the meansfor the electrical pulse bursts to be applied to the patient's skin.Also, the conductive rollers 830′ provide the mechanism for the heatingradio frequency signal to be directly applied to the patient's skin. Therollers 830′ are preferably metal rollers or conductive plastic rollers.Also shown in FIG. 30 are coaxial cables 3010 that provide the path forthe electrical pulse bursts and the heating radio frequency signal to beprovided to the rollers 830′ disposed on the head of the probe. FIG. 31shows one possible way in which these signals can be provided to therollers 830′, whereby a radio frequency generator 3110 outputs a radiofrequency signal, which then passes through a first filter 3120, andthen on to the coaxial line 3010. A electrical signal burst generator3130 outputs bursts of electrical pulses, which then pass through asecond filter 3140, and then on to the coaxial line 3010. The firstfilter 3120 has a bandwidth such that it blocks the electrical pulsebursts from entering the radio frequency generator 3110, and the secondfilter 3150 has a bandwidth such that it blocks the heating radiofrequency signal from entering the electrical signal burst generator3140. One possible circuit implementation of the electrical signal burstgenerator 3140 is shown in FIG. 4, for example.

As described with respect to an earlier embodiment, a preferredfrequency of each of the electrical pulses in the bursts of electricalpulses is between 2500 and 3000 Hz, and thus the first filter 3120 maybe configured to block out this particular frequency range (but to passthrough frequencies greater than 1 MHz). Similarly, the second filter3150 may be configured to block out frequency ranges greater than 1 MHzwhile allowing lower frequency signals to pass therethrough (e.g., it isa low-pass filter).

A fifteenth embodiment of the invention will be described below, withreference to FIGS. 32A-C, 33A, 33B, and 33A-C. The fifteenth embodimentprovides an alternative way of providing a substance to the skin of apatient by way of a component coupled to a head of a probe that provideselectrical pulses and/or mechanical vibrations to the patient's skin. Inthat regard, the fifteenth embodiment is similar to the thirteenthembodiment described previously, but whereby the way that askin-treating substance is applied to the skin is done in a differentmanner.

FIG. 32A shows a side sectional view of a probe head 3210 that iscoupled to a head attachment 3220. The head attachment 3220 ispreferably made from polypropylene (it can be a plastic component), andit has nine cylindrical openings 3222 that allow nine separatecylindrical sponges to be fitted therein. FIG. 32B shows a front view ofthe head attachment 3220, and FIG. 32C shows a side sectional view ofone of the cylindrical openings 3222 of the attachment head 3220,whereby a cylindrical sponge 3224 is fitted within the cylindricalopening 3222. Alternatively to using cylindrical sponges, cotton gauzesor hydrogel pads can be fitted within the cylindrical openings 3222, ora combination of these components may be used (e.g., three gauze pads,three sponges, and three hydrogel pads). The attachment head 3220 isshown having nine separate cylindrical openings 3220 for the case wherethere are nine electrodes disposed on the face of the probe, wherebyFIG. 32A shows three of the electrodes 3230 in a side view (the otherelectrodes on the face of the probe are blocked from view, but see FIG.2C for the disposition of the nine electrodes).

Each of the nine electrodes on the face of the probe is disposed at oneend of the cylindrical opening 3222, whereby the sponge 3224 extendsslightly out from the other end of the cylindrical opening 3222, as seenbest in FIG. 32B. That way, the sponge is made to be in contact with anarea of the patient's skin to be treated by way of the probe. Eachsponge 3222 is soaked with a substance to be applied to the patient'sskin, whereby one may have hydrogel pads soaked with 4% lidocaine, forexample. With the electrical pulses being applied to the patient's skinby way of the electrical pulses (that are indirectly connected to thepatient's skin by way of the sponges 3222) and/or by the mechanicalvibrations, the substance provided on the sponges 3222 is readilyabsorbed within the patient's skin.

In a preferred configuration, the attachment head 3220 is a disposablecomponent, that can be thrown away when after a patient has beentreated. The attachment head 3220 may be detachably coupled to the probehead 3210 in any of a variety of ways, such as by using a snap-oncoupling, or by other ways that have been described previously withrespect to other embodiments. Of course, if the disposition and numberof electrodes is different on the probe head 3210, the disposition andnumber of openings on the attachment 3220 will change to accommodatethat particular disposition.

FIGS. 33A and 33B show a second type of electrode disposition, in whicha central electrode 3310 is provided beneath a centrally-positionedsponge 3320, and in which peripheral electrodes 3330 are providedbeneath a peripherally-positioned sponge 3340. In this configuration,the probe head 3305 has a circular shape, whereby the attachment head3350 has an inner cylindrical opening 3360 for accommodating thecentrally-positioned sponge 3320, and an outer cylindrical opening 3370for accommodating the peripherally-positioned sponge 3340. FIG. 33Ashows a side sectional view of the probe head 3305 with the attachmenthead 3350 coupled thereto, and FIG. 33B shows a front view of theattachment head 3350 with the sponges fitted within the respectiveopenings of the attachment head 3350.

FIGS. 34A-34C show a third type of electrode disposition on a probe head3405. This disposition corresponds to the one shown in FIGS. 17 and 18of the drawings, for example, whereby there is not anycentrally-positioned electrode on the probe head 3405. In thisconfiguration, the three electrodes 3410 are provided beneath therespective three cylindrical openings 3420 of the attachment head 3430,whereby the attachment head 3430 may be made out of polypropylene, forexample. Each of the cylindrical openings 3420 may be filled with asponge or gauze that has been soaked with a substance to the applied tothe patient's skin. FIG. 34A shows a sectional side view of the probehead 3405 with the attachment head 3430 detachably attached thereto,FIG. 34B shows a front view of the attachment head 3430 (without anysponges provided in the openings 3420), and FIG. 34C shows a sidesectional view of one cylindrical opening 3420 with a sponge 3450 fittedtherein.

A sixteenth embodiment of the invention will be described in detailbelow. Several measurements carried out by the inventor on human skinand on rat skin have demonstrated that after microdermabrasion isperformed on the skin, it is possible to obtain a significant transferrate of drugs composed by macromolecules, by using a low current valueat a time when the drug is applied to the skin. In a preferredimplementation of the sixteenth embodiment, the current value is keptbelow a peak value of 15 milliampere×square centimeter.

Measurement of voltage and current of a burst of electrical pulses whenapplied to the skin has been performed, and an optimal value has beendiscovered that allows for a significant transfer rate for the drug tobe absorbed into the skin. It has been discovered that when the skinimpedance is lower than 500 Ohm×square centimeter, the transfer rate isoptimal. Furthermore, when the skin impedance is higher than 5000Ohm×square centimeter, the transfer rate is relatively unstable andlimited to drugs having small molecules. In the range between 500Ohm×square centimeter and 5000 Ohm×square centimeter, the transfer rateis not as optimal (e.g., less stable than the lower range), but it stillmay provide a useful drug transfer rate for certain purposes. This givesa criteria in order to verify if the microdermabrasion (or other type oftreatment for decreasing the impedance of the corneum stratum) has beenperformed in an optimal manner.

In one possible implementation of the sixteenth embodiment of theinvention, a simultaneous impedance measurement together with theapplication of electrical bursts of pulses to the skin, gives real timedata that enables the identification of portions of the skin where theimpedance is high, signaling the insufficient transfer rate of drugs,and the need for an additional microdermabrasion skin treatment (orother type of treatment to remove more of the corneum stratum). Thisavoids the possible mistake of an improper amount of drug quantitydelivered to the skin, which could be dangerous when delivered in aninsufficient amount or in a too high dosage amount that could bringabout health risks.

One solution to obtain the measurement of the skin impedance when aburst of electrical pulses is applied to the skin, is to measure the rmsvoltage (volt), measure the rms current (milliampere), provide the twomeasured values to a microprocessor, and divide the two values by way ofthe microprocessor. The resulting value obtained is the skin impedancevalue (ohm).

Another solution is a simplification of the previous one and is based onthe stabilization of the current value applied to the skin. If thecurrent value is set at a predetermined value by an instrument, forexample, there is no need to measure the current, whereby the impedancevalue is simply proportional to the voltage value. In this way, amicroprocessor for performing a division operation is not needed, andthe measurement can be done with a standard analog or digital voltagemeasurement circuit. The measurement is preferably done directly at ornear the electrodes that provide the drug to the patient's skin.

A control of the current value when the bursts of electrical pulses areapplied to the skin is important because it is well known in the artthat the flow of ions into the skin is proportional to the value of thecurrent.

Several solutions can be used for stabilizing the current value. In afirst solution in order to obtain such a result, a modification in theelectrical pulse creation circuit (see FIG. 4) of the previousembodiments is utilized for this embodiment. Due to the fact that, in atransformer, it is well known that the current in the primary winding isequal to the current in the secondary winding multiplied by the turnratio, a mechanism that fixes the primary current to a predeterminedvalue during the conduction of the transistor is utilized. A relativelysimple solution is to utilize a resistor R in series to the primarywinding 420 of the transformer, as shown in the pulse generator circuit400A in FIG. 35. In a preferred implementation of the sixteenthembodiment, a 12 ohm resistor may be utilized, and alternatively aresistor having a resistance between 5 ohms and 100 ohms may be utilizedfor resistor R.

If the supply voltage is sufficiently high, e.g., around 12 Volts orhigher, and the voltage during the pulse across the transformer andacross the transistor is sufficiently low, e.g., around 1 Volts orlower, the current can be calculated to be the supply voltage divided bythe resistance value R with an error of +/−10%. In FIG. 35, the supplyvoltage is denoted by the “+” symbol above the resistance value R.

Such a modified transformer circuit is able to provide bursts ofsquare-like current pulses when the skin impedance is lower than 2000ohm×square centimeter, which is desirable to provide a significanttransfer rate of a drug to be applied to a patient's skin. The samecircuit is able to provide exponential decay pulses when the impedanceis higher than 10000 Ohm×square centimetre, which could happen duringthe first pulse. When the impedance is lower than 2000 ohm×squarecentimeter, the pulses are still exponential decay curves, but due tothe longer decay time because of the lower impedance, the delay curve isclose to a square with an error less than 20%.

Another possible solution is to drive the skin directly with a circuitthat provides bursts of alternately polarity, stabilized current pulses,such as the ones shown in FIG. 36. The pulses in each burst alternatebetween a current output of +lo amperes and −lo amperes, and thus are“stabilized” at one of these two current values during the entireduration of each pulse. One relatively simple solution is to use anoperational amplifier configured as a current generator whose output iscoupled to the skin directly or through an insulation transformer. Forexample, the operational amplifier and/or insulation transformer may bedirectly coupled to the electrodes within the head of the probe.

Although the alternately-polarized square current pulse implementationhas been determined by the inventor to be less effective in transdermaldrug delivery when the skin impedance is relatively high, it gives ahigher reproducibility of dose delivery when the skin has beenpreviously treated and when the skin impedance is less than 1000Ohm×square centimeter.

An advantage of using the alternately-polarized square stabilizedcurrent pulses is that the measurement of the skin impedance can beperformed relatively easily, as explained above with respect to the useof an operational amplifier and/or insulation transformer.

In a seventeenth embodiment of the invention, a further improvement ofthe transdermal flow of a drug to a patient's skin is accomplished bythe introduction of an additional waveform between the bursts of pulses,in order to minimize the time where there is no flow of ions to thepatient's skin. This additional waveform is preferably symmetrical, andhas a low rise time in order to avoid a sensation of pain that couldotherwise occur between the bursts that could not be masked bymechanical vibrations that may be applied to the skin at the same time(as described previously with respect to other embodiments of theinvention).

Two possible waveform meet such a criteria: the first is the use ofalternate polarity square pulses between each of the adjacent bursts ofpulses, as shown by pulses 3710 and 3720 in FIG. 37. Such alternatepolarity square pulses meet the criteria previously described because notransition occurs between the adjacent bursts of pulses, and so noadditional pain sensation is generated for the patient (a desirablefeature), and whereby a current flow occurs between the pulses thatdrive the ions into the skin (in order to reduce the pain sensation tothe patient). The second possible waveform is a sinusoidal waveform thatoccurs between each of the adjacent burst of pulses as shown bysinusoidal waveforms 3810 and 3820 in FIG. 38, or by waveforms 3910 and3920 in FIG. 39 or by waveforms 4010 and 4020 in FIG. 40. The sinusoidis a waveform with a minimum slope, and for this reason it generates aminimum amount of additional pain to the patient in between theapplication of the bursts of pulses to the patient's skin. Thus, theadditional pulses utilized in the seventeenth embodiment operate as‘buffers’ to reduce the pain sensation to the patient in between theapplication of the bursts of pulses provided to the patient's skin.

An eighteenth embodiment of the invention will be described below withreference to FIGS. 41, 42 and 43. In the eighteenth embodiment, thepulse generator is the same as one of the types described in theprevious embodiments, but whereby the probe differs from the onesdescribed with respect to the previous embodiments.

In the eighteenth embodiment, the probe 4100 comprises a flexible tape4105 with stripe-shaped cavities (or cylindrical-shaped cavities orrectangular-shaped cavities). The tape 4105 may be implemented as arubber tape, plastic tape, or of other flexible material. In each cavity4110, a gauze stripe 4115 is inserted. Between the gauze stripe and thebottom of the cavity (the bottom end being the end of the cavity that isfurthest from the patient's skin when the tape 4105 is applied to thepatient's skin), an electrically conductive element 4125, such as awire, is inserted. The electrically conductive elements 4125 in thefirst, third, fifth and seventh cavities are connected together to eachother at the bottom end of those cavities, to thereby form a first wiredconnection 4120. The electrically conductive elements 4125 in thesecond, fourth, sixth and eighth cavities are connected together to eachother at the top end of those cavities, to thereby form a second wiredconnection 4130. Between the cavities, the rubber tape is coated withadhesive 4140 in order to releasably affix the rubber tape to thepatient's skin 4300. In operation, electrical pulses are provided fromthe pulse generator to the first, third, fifth and seventh cavities viathe first wired connection, and electrical pulses are provided from thepulse generator to the second, fourth, sixth and eighth cavities via thesecond wired connection.

In one possible implementation, the width of each cavity is 5millimeters and the adhesive stripe width is 5 millimeters, wherebyother sizes (e.g., cavity width of from 3 to 12 millimeters, adhesivestripe width of from 3 to 12 millimeters) may be utilized whileremaining within the spirit and scope of the invention. The overall sizeof the rubber tape can vary based upon the size of the area of the skinto be treated, with such a variation of rubber tape size of between20×20 millimeters to 500×500 millimeters. FIG. 41 shows a top down viewof the probe 4100, FIG. 42 shows a sectional view of the probe 4100(taken along line 42-42 in FIG. 41), and FIG. 43 shows a side view ofthe probe 4100 attached to the patient's skin 4300.

The gauze stripes are soaked with the drug to be absorbed before theapplication of the drug to the patient, whereby the soaked gauze stripesare then fitted into the respective cavities of the rubber tape.Alternatively, the drug has been already introduced in each gauze stripeduring the manufacturing of the probe, and whereby the gauze stripes arethen fitted into the cavities and the probe is sealed to preventcontamination with the environment (e.g., placed in a sealed plasticcontainer). In that case, the rubber tape is disposable, for one timeuse (to be discarded after that one time use).

Before the application of the tape onto the patient skin, a dermabrasionmay be carried out as described before with respect to previousembodiments, in order to prepare the skin better for reception of thedrug.

A nineteenth embodiment of the invention will be described below withreference to FIGS. 44 and 45. The nineteenth embodiment is similar tothe eighteenth embodiment, with the addition of piezoelectrictransducers 4410 as described in FIGS. 44 and 45. The function of thetransducers 4410 is to apply vibrations to the skin in order to decreasethe undesired sensation of the electric current to the patient. Thetransducers 4410 are placed at different positions on the tape 4105, andare shown in FIGS. 44 and 45 as disposed on the tape 4105 in twocolumns, with four transducers per column. The characteristics of thevibrations applied to the skin is the same as described with respect toprevious embodiments.

A twentieth embodiment of the invention will be described below withreference to FIGS. 41 to 48. In the twentieth embodiment, the pulsegenerator is the same as one of the types described in the previousembodiments, but whereby the probe differs from the ones described withrespect to the previous embodiments.

In the twentieth embodiment, the probe comprises a flexible tape 4100with round-shaped cavities (or cylindrical-shaped cavities orrectangular-shaped cavities), such as shown in FIG. 41. The tape 4100may be implemented as a rubber tape, plastic tape, silicon tape or ofother flexible material. In each cavity 4110, a gauze is inserted.Between the gauze stripe and the bottom of the cavity (the bottom endbeing the end of the cavity that is furthest from the patient's skinwhen the tape 4100 is applied to the patient's skin), an electricallyconductive element, such as a wire, is inserted. The electricallyconductive elements in the same horizontal row are connected together toeach other at the bottom end of those cavities, to thereby form a firstwired connection 4120. The electrically conductive elements in the samevertical row are connected together to each other at the top end ofthose cavities, to thereby form a second wired connection 4130. Betweenthe cavities, the rubber tape is coated with adhesive 4140 in order toreleasably affix the rubber tape to the patient's skin. In operation,electrical pulses are provided from the pulse generator in sequence toelectrical pulse lines AA′, AB′, AC′, AD′, BA′, BB′, BC′, BD′, CA′, CB′,CD′, DA′, DB′, DC′, DD′. FIG. 46 shows a top-down view of a probe 4810with electrodes 4820, whereby electrical pulse lines A, B, C, D, A′, B′,C′ and D′ are also shown in that figure. FIG. 47 is a sectional view ofthe probe taken along line 47-47, and FIG. 48 shows the sequence ofpulses provided by the pulse generator 4800 to the electrical pulselines A-D and A′-D′. A switch or multiplexer (not shown) may be providedto sequentially switch the electrical pulse lines A-D and A′-D′ to/fromthe pulse generator 4800. By providing the electrical pulses to theelectrical pulse lines in sequential order as described above, the probeaccording to the twentieth embodiment is better able to control thecurrent density to the patient's skin than in the previously-describedembodiments.

In one possible implementation, the width of each cavity is 5millimeters and the adhesive stripe width is 5 millimeters, wherebyother sizes (e.g., cavity width of from 3 to 12 millimeters, adhesivestripe width of from 3 to 12 millimeters) may be utilized whileremaining within the spirit and scope of the invention. The overall sizeof the rubber tape can vary based upon the size of the area of the skinto be treated, with such a variation of rubber tape size of between20×20 millimeters to 500×500 millimeters.

The gauze stripes are soaked with the drug to be absorbed before theapplication of the drug to the patient, whereby the soaked gauze stripesare then fitted into the respective cavities of the rubber tape.Alternatively, the drug has been already introduced in each gauze stripeduring the manufacturing of the probe, and whereby the gauze stripes arethen fitted into the cavities and the probe is sealed to preventcontamination with the environment (e.g., placed in a sealed plasticcontainer). In that case, the rubber tape is disposable, for one timeuse (to be discarded after that one time use).

Before the application of the tape onto the patient skin, a dermabrasionmay be carried out as described before with respect to previousembodiments, in order to prepare the skin better for reception of thedrug.

A twenty-first embodiment of the invention will be described below withreference to FIGS. 44 to 48. The twenty-first embodiment is similar tothe twentieth embodiment, with the addition of piezoelectric transducers4410 as described in FIGS. 44 and 45. The function of the transducers4410 is to apply vibrations to the skin in order to decrease theundesired sensation of the electric current to the patient. Thetransducers 4410 are placed at different positions on the tape 4100, andare shown in FIGS. 44 and 45 as disposed on the tape 4100 in twocolumns, with four transducers per column. The characteristics of thevibrations applied to the skin is the same as described with respect toprevious embodiments.

By providing the electrical pulses to the electrical pulse lines insequential order as described above, the probe according to thetwentieth and twenty-first embodiments is better able to control thecurrent density to the patient's skin then in the previously-describedembodiments. The switch is preferably an electronic switch controlled bya microprocessor.

In a twenty-second embodiment, which is similar to the twentiethembodiment, instead of having one pulse generator that is switched tothe eight electronic lines A, B, C, D, A′, B′, C′, D′ in the sequence asprovided above, there is provided eight separate pulse generators thatare respectively connected to the eight electronic lines A, B, C, D, A′,B′, C′, D′, whereby a microprocessor provides the control for switchingon the pulse generators in a particular sequence (e.g., AA′, AB′, AC′,AD′, BA′, BB′, BC′, BD′, CA′, CB′, CD′, DA′, DB′, DC′, DD, AA′, AB′, . .. ). For the particular sequence described above, at any point in time,only two of the pulse generators are switched on to provide electronicpulses to the line that it is coupled to, whereby the other six pulsegenerators are switched off. The twentieth and twenty-second embodimentshave been described with respect to eight pulse generators and eightelectronic pulse lines, whereby one skilled in the art will recognizethat any number of pulse generators and electronic pulse lines may beutilized, depending upon the number of rows and columns in the matrix ofelectrodes provided on the probe. Also, in an alternativeimplementation, more than two electronic pulse lines and/or pulsegenerators (e.g., all the odd lines or all the even ones)) may beenabled at any point in time, to simultaneously provide more than twoelectronic pulses to a patient's skin in a controlled manner. Thus, inone alternative implementation, the odd electronic pulse lines (A, C,A′, C′) are switched on at the same time to provide electronic pulses tothe patient's skin, and then the even electronic pulse lines (B, D, B′,D′) are switched on, etc.

In the twentieth, twenty-first and twenty-second embodiments, thepreferred switch rate (the rate at which the lines are switched) is 200Hz, and the preferred dwell time (the time which any particular isconnected to the pulse generator) is 5 milliseconds. A preferred switchrate “range” is 10 to 2000 Hz, and a preferred dwell time “range” is 0.5millisecond to 100 milliseconds, whereby other switch rate and dwelltime ranges are possible while remaining within the spirit and scope ofthe invention.

Different embodiments of the present invention have been describedaccording to the present invention. Many modifications and variationsmay be made to the techniques and structures described and illustratedherein without departing from the spirit and scope of the invention.Accordingly, it should be understood that the apparatuses describedherein are illustrative only and are not limiting upon the scope of theinvention. For example, the frequency of the mechanical vibration andthe frequency of the bursts of electronic pulses may be the same, asdescribed above with respect to several different embodiments, or theymay be an integer multiple or submultiple of each other. For example, anelectronic pulse burst frequency of 50 Hz may be utilized together witha mechanical vibration of 100 Hz, and still one would achieve an effectof increased absorption and decrease in skin sensitivity (e.g., loweringof the pain) to the patient. Alternatively, an electronic burstfrequency of 200 Hz may be utilized together with a mechanical vibrationof 100 Hz, and still one would achieve an effect of increased absorptionand decrease in skin sensitivity. Also, the plate on which theelectrodes are disposed on the probe in certain embodiments may be asterilized disposable part (e.g., removed from a sterilized containerand then affixed to the head of the probe). In this implementation, whenone is finished treating a patient, the disposable plate is removed fromthe probe and discarded, and then a new sterilized plate is affixed tothe probe (with the electrodes provided thereon) in order to treatanother patient. By such an implementation, this greatly reduces thepossibility of contamination between different patients, since theportion of the probe directly in contact with each patient is discardedafter treatment of each patient.

1. An apparatus for performing transdermal drug delivery to be providedto a patient's skin, comprising: a dermabrasion unit for performing adermabrasion treatment of the patient's skin so as to lower a skinimpedance to below a predetermined value; and a probe configured toprovide at least one burst of electrical pulses to the patient's skin,the probe including: a transformer configured to create the at least oneburst of electrical pulses to be provided to the patient's skin, whereineach pulses in the at least one burst of electrical pulses is stabilizedwith respect to a current amount by way of a resistor coupled betweenthe transformer and a supply voltage; and at least one electrodeprovided on a head of the probe and configured to receive the at leastone burst of electrical pulses from the transformer and to provide theat least one burst of electrical pulses to the patient's skin; means fordetermining an impedance of the patient's skin at a same time that theat least one burst of electrical pulses is provided to the patient'sskin; and means for controlling an amount of current provided in the atleast one burst of electrical pulses so as to control the impedance ofthe patient's skin to be below a predetermined impedance value, whereina second resistor is connected in parallel with a secondary winding ofthe transformer.
 2. The apparatus according to claim 1, wherein thepredetermined impedance value is 500 Ohms per square centimeter.
 3. Theapparatus according to claim 1, wherein the predetermined impedancevalue is 2000 Ohms per square centimeter.
 4. The apparatus according toclaim 1, wherein the at least one burst of electrical pulses comprises aplurality of square-shaped, current stabilized pulses.
 5. The apparatusaccording to claim 1, wherein the least one burst of electrical pulsescomprises a plurality of alternately-polarized, current-stabilizedpulses.
 6. The apparatus according to claim 1, wherein the means fordetermining determines the impedance by measuring an rms voltage on thepatient's skin, measuring an rms current on the patient's skin, anddividing the rms voltage by the rms current.
 7. The apparatus accordingto claim 6, wherein the means for determining comprises amicroprocessor.
 8. An apparatus for performing transdermal drug deliveryto be provided to a patient's skin, comprising: a dermabrasion unit forperforming a dermabrasion treatment of the patient's skin so as to lowera skin impedance to below a predetermined value; and a probe configuredto provide at least one burst of electrical pulses to the patient'sskin, the probe including: a transformer configured to create the atleast one burst of electrical pulses to be provided to the patient'sskin, wherein each pulses in the at least one burst of electrical pulsesis stabilized with respect to a current amount by way of a resistorcoupled between the transformer and a supply voltage; at least oneelectrode provided on a head of the probe and configured to receive theat least one burst of electrical pulses from the transformer and toprovide the at least one burst of electrical pulses to the patient'sskin, wherein the least one burst of electrical pulses comprises aplurality of alternately-polarized, current-stabilized pulses andwherein a second resistor is connected in parallel with a secondarywinding of the transformer.